Exercise Modulates Adiposity-induced Immune Dysfunction in NSCLC and Non-tumor-Bearing Lungs: Implications for Lung Cancer Therapy and Interception.

OBJECTIVE

To determine whether physical activity modulates adiposity-driven immune suppression in the lung and tumor microenvironment to restore antitumor immunity.

BACKGROUND

Obesity is associated with immune dysfunction that supports lung cancer progression, namely reduced cytotoxic T-cell activity and expansion of suppressor populations. These alterations extend to the lung, the site of new and metastatic tumors. Although exercise improves metabolic and inflammatory profiles, its impact on adiposity-associated immune dysregulation in these compartments remains unclear.

METHODS

Obese and lean mice were implanted with Lewis lung carcinomas under sedentary conditions or with exercise wheel access. Exercise effects on the tumor and infiltrating leukocytes were assessed by RNA sequencing and flow cytometry. The lungs of obese and lean tumor-naïve mice with and without exercise were also characterized by flow, as were bronchoalveolar lavage samples from patients (n = 73) stratified by total fat area and physical activity with multivariable adjustments.

RESULTS

Obese mice allowed voluntary exercise displayed less profound enhancement of Tregs and potentially suppressive myeloid cells and fewer CD8⁺ T-cell deficits in the tumor and lung. These mice displayed significant delays in tumor growth, while muted effects were seen in lean mice. Transcriptomic modulation consistent with altered vascular and metabolic programs was also evident in active obese mice. In human bronchoalveolar lavage, physical activity was also linked to reductions in Programmed Death receptor 1⁺ Tregs and suppressive myeloid cells enhanced by adiposity.

CONCLUSIONS

Exercise may reverse adiposity-associated immune suppression in the lung and tumor microenvironments to complement lung cancer interception and treatment strategies.